Symptoms
Symptoms of overdose may include hypotension, cardiac insufficiency, bradycardia and bradyarrhythmia, cardiac conduction disturbances and bronchospasm.
Management
Care should be provided at a facility that can provide appropriate supporting measures, monitoring and supervision.
Atropine, adrenostimulating drugs or pacemaker to treat bradycardia and conduction disorders.
Hypotension, acute cardiac failure, and shock to be treated with suitable volume expansion, injection of glucagon (if necessary, followed by an intravenous infusion of glucagon), intravenous administration of adrenostimulating drugs such as dobutamine, with α1 receptor agonistic drugs added in presence of vasodilation. Intravenous use of Ca2+ can also be considered.
Bronchospasm can usually be reversed by bronchodilators.
Беталок I.V. Injection, as with other beta blockers, should not be used in patients with any of the following:
-
- Hypotension.
- AV block of second- or third-degree.
- Decompensated cardiac failure (pulmonary oedema, hypoperfusion or hypotension).
- Continuous or intermittent inotropic therapy acting through beta-receptor agonism.
- Bradycardia (<45 bpm).
- Sick sinus syndrome (unless a permanent pacemaker is in place).
- Cardiogenic shock.
- Severe peripheral arterial circulatory disorder.
- Untreated phaeochromocytoma.
- Metabolic acidosis.
Known hypersensitivity to any component of Беталок I.V. Injection or other beta-blockers.
Беталок I.V. Injection is also contra-indicated when suspected acute myocardial infarction is complicated by bradycardia (<45 bpm), first-degree heart block or systolic blood pressure <100 mmHg and/or severe heart failure.
Not applicable.
The following events have been reported as adverse events in clinical trials or reported from routine use.
The following definitions of frequencies are used:
Very common (>1/10), common (>1/100 to <1/10), uncommon ((>1/1,000 to <1/100), rare ((>1/10,000 to <1/1,000) and very rare (<1/10,000).
| System Organ Class | Frequency | Undesirable Effect |
| Infections and infestations | Very rare | Gangrene in patients with pre existing severe peripheral circulatory disorders |
| Blood and lymphatic system disorders | Very rare | Thrombocytopenia |
| Psychiatric disorders | Uncommon | Depression, insomnia, nightmares |
| Rare | Nervousness, anxiety | |
| Very rare | Confusion, hallucinations | |
| Nervous system disorders | Common | Dizziness, headache |
| Uncommon | Concentration impairment, somnolence, paraesthesiae | |
| Very rare | Amnesia/memory impairment, taste disturbances | |
| Eye disorders | Rare | Disturbances of vision, dry and/or irritated eyes, conjunctivitis |
| Ear and labyrinth disorders | Very rare | Tinnitus |
| Cardiac disorders | Common | Bradycardia, palpitations |
| Uncommon | Deterioration of heart failure symptoms, cardiogenic shock in patients with acute myocardial infarction*, first degree heart block | |
| Rare | Disturbances of cardiac conduction, cardiac arrhythmias, increased existing AV block | |
| Vascular disorders | Common | Postural disorders (very rarely with syncope) |
| Rare | Raynauds phenomenon | |
| Very rare | Increase of pre-existing intermittent claudication | |
| Respiratory, thoracic and mediastinal disorders | Common | Dyspnoea on exertion |
| Uncommon | Bronchospasm | |
| Rare | Rhinitis | |
| Gastrointestinal disorders | Common | Nausea, abdominal pain, diarrhoea, constipation |
| Uncommon | Vomiting | |
| Rare | Dry mouth | |
| Hepatobiliary disorders | Very rare | Hepatitis |
| Skin and subcutaneous tissue disorders | Uncommon | Rash (in the form of psoriasiform urticaria and dystrophic skin lesions), increased sweating |
| Rare | Loss of hair | |
| Very rare | Photosensitivity reactions, aggravated psoriasis | |
| Musculoskeletal and connective tissue disorders | Very rare | Arthralgia |
| Uncommon | Muscle cramps | |
| Reproductive system and breast disorders | Rare | Impotence/sexual dysfunction |
| General disorders and administration site disorders | Very common | Fatigue |
| Common | Cold hands and feet | |
| Uncommon | Precordial pain, oedema | |
| Investigations | Uncommon | Weight gain |
| Rare | Liver function test abnormalities, positive anti-nuclear antibodies (not associated with SLE). |
* Excess frequency of 0.4 % compared with placebo in a study of 46,000 patients with acute myocardial infarction where the frequency of cardiogenic shock was 2.3 % in the metoprolol group and 1.9 % in the placebo group in the subset of patients with low shock risk index. The corresponding excess frequency for patients in Killip class I was 0.7% (metoprolol 3.5% and placebo 2.8%). The shock risk index was based on the absolute risk of shock in each individual patient derived from age, sex, time delay, Killip class, blood pressure, heart rate, ECG abnormality, and prior history of hypertension. The patient group with low shock risk index corresponds to the patients in which metoprolol is indicated for use in acute myocardial infarction.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme.
Website: www.mhra.gov.uk/yellowcard.
Pre-clinical information has not been included because the safety profile of metoprolol tartrate has been established after many years of clinical use. Please refer to section 4.
Control of tachyarrhythmias, especially supraventricular tachyarrhythmias.
Early intervention with Беталок I.V. Injection in acute myocardial infarction reduces infarct size and the incidence of ventricular fibrillation. Pain relief may also decrease the need for opiate analgesics.
Беталок I.V. Injection has been shown to reduce mortality when administered to patients with acute myocardial infarction.
Pharmacotherapeutic group: Beta blocking agents, selective
ATC code: C07AB02
Mechanism of action
Metoprolol is a competitive beta-adrenoceptor antagonist. It acts preferentially to inhibit beta-adrenoceptors (conferring some cardioselectivity), is devoid of intrinsic sympathomimetic activity (partial agonist activity) and possesses beta-adrenoceptor blocking activity comparable in potency with propranolol.
Pharmacodynamic effects
A negative chronotrophic effect on the heart is a consistent feature of metoprolol administration. Thus, cardiac output and systolic blood pressure rapidly decrease following acute administration.
Clinical efficacy and safety
The intention to treat trial COMMIT included 45,852 patients admitted to hospital within 24 hours of the onset of symptoms of suspected acute myocardial infarction with supporting ECG abnormalities (i.e. ST elevation, ST depression or left bundle-branch block). Patients were randomly allocated to metoprolol (up to 15 mg intravenous then 200 mg oral) or placebo and treated until discharge or up to 4 weeks in hospital. The two co-primary outcomes were: (1) composite of death, reinfarction or cardiac arrest; and (2) death from any cause during the scheduled treatment period. Neither of the co-primary outcomes was significantly reduced by metoprolol. However, metoprolol treatment was associated with fewer people having reinfarction and ventricular fibrillation but an increased rate of cardiogenic shock during the first day after admission. There was substantial net hazard in haemodynamically unstable patients. There was moderate net benefit in those who were stable, particularly after days 0-1.
Biotransformation
Metoprolol undergoes oxidative metabolism in the liver primarily by the CYP2D6 isoenzyme.
Elimination
Metoprolol is eliminated mainly by hepatic metabolism, the average elimination half-life is 3.5 hours (range 1-9 hours). Rates of metabolism vary between individuals, with poor metabolisers (approximately 10%) showing higher plasma concentrations and slower elimination than extensive metabolisers. Within individuals, however, plasma concentrations are stable and reproducible.
When treating patients with suspected or definite myocardial infarction the haemodynamic status of the patient should be carefully monitored after each of the three 5 mg intravenous doses. The second or third dose should not be given if the heart rate is <40 beats/min, the systolic blood pressure is <90 mmHg and the P-Q time is >0.26 sec, or if there is any aggravation of dyspnoea or cold sweating.
Беталок I.V. Injection, as with other beta blockers:
- should not be withdrawn abruptly during oral treatment. When possible, Беталок I.V. Injection should be withdrawn gradually over a period of 10 - 14 days, in diminishing doses to 25 mg daily for the last 6 days. During its withdrawal patients should be kept under close surveillance, especially those with known ischaemic heart disease. The risk for coronary events, including sudden death, may increase during the withdrawal of beta-blockade.
- must be reported to the anaesthetist prior to general anaesthesia. It is not generally recommended to stop Беталок I.V. Injection treatment in patients undergoing surgery. If withdrawal of metoprolol is considered desirable, this should, if possible, be completed at least 48 hours before general anaesthesia. Routine initiation of high-dose metoprolol to patients undergoing non-cardiac surgery should be avoided, since it has been associated with bradycardia, hypotension, stroke and increased mortality in patients with cardiovascular risk factors. However in some patients it may be desirable to employ a beta-blocker as premedication. In such cases an anaesthetic with little negative inotropic activity should be selected to minimise the risk of myocardial depression.
- although contra-indicated in severe peripheral arterial circulatory disturbances , may also aggravate less severe peripheral arterial circulatory disorders.
- may be administered when heart failure has been controlled. Digitalisation and/or diuretic therapy should also be considered for patients with a history of heart failure, or patients known to have a poor cardiac reserve. Беталок I.V. Injection should be used with caution in patients where cardiac reserve is poor.
- may cause patients to develop increasing bradycardia, in such cases the Беталок I.V. Injection dosage should be reduced or gradually withdrawn.
- due to the negative effect on conduction time, should only be given with caution to patients with first-degree heart block.
- may increase the number and duration of angina attacks in patients with Prinzmetal's angina, due to unopposed alpha-receptor mediated coronary artery vasoconstriction. Беталок I.V. Injection is a beta1-selective beta-blocker; consequently, its use may be considered although utmost caution must be exercised.
- may mask the early signs of acute hypoglycaemia, in particular tachycardia. During treatment with Беталок I.V. Injection, the risk of interfering with carbohydrate metabolism or masking hypoglycaemia is less than with non-selective beta-blockers.
- may mask the symptoms of thyrotoxicosis.
- may increase both the sensitivity towards allergens and the seriousness of anaphylactic reactions.
Although cardioselective beta-blockers may have less effect on lung function than non-selective beta-blockers, as with all beta-blockers, these should be avoided in patients with reversible obstructive airways disease unless there are compelling clinical reasons for their use. When administration is necessary, these patients should be kept under close surveillance. The use of a beta2-bronchodilator (e.g. terbutaline) may be advisable in some patients. The dosage of the beta2-agonist may require an increase when treatment with Беталок I.V. Injection is commenced.
The label shall state - “Use with caution in patients who have a history of wheezing, asthma or any other breathing difficulties, see enclosed user leaflet.â€
Like all beta-blockers, careful consideration should be given to patients with psoriasis before Беталок I.V. Injection is administered.
In patients with a phaeochromocytoma, an alpha-blocker should be given concomitantly.
In labile and insulin-dependent diabetes it may be necessary to adjust the hypoglycaemic therapy.
Intravenous administration of calcium antagonists of the verapamil type should not be given to patients treated with beta-blockers.
Беталок I.V. Injection has minor influence on the ability to drive and use machines. It should be taken into account that occasionally dizziness or fatigue may occur.
Posology
The dose must always be adjusted to the individual requirements of the patient. The following are guidelines:
Cardiac arrhythmias:
Initially up to 5 mg injected intravenously at a rate of 1-2 mg per minute. The injection can be repeated at 5 minute intervals until a satisfactory response has been obtained. A total dose of 10-15 mg generally proves sufficient.
Because of the risk of a pronounced drop of blood pressure, the I.V. administration of Беталок I.V. Injection to patients with a systolic blood pressure below 100 mmHg should only be given with special care.
During Anaesthesia:
2-4 mg injected slowly I.V. at induction is usually sufficient to prevent the development of arrhythmias during anaesthesia. The same dosage can also be used to control arrhythmias developing during anaesthesia. Further injections of 2 mg may be given as required to a maximum overall dose of 10 mg.
Myocardial infarction:
Intravenous Беталок I.V. Injection should be initiated in a coronary care or similar unit when the patient's haemodynamic condition has stabilised. Therapy should commence with 5 mg I.V. every 2 minutes to a maximum of 15 mg total as determined by blood pressure and heart rate. The second or third dose should not be given if the systolic blood pressure is <90 mmHg, the heart rate is <40 beats/min and the P-Q time is >0.26 seconds, or if there is any aggravation of dyspnoea or cold sweating. Oral therapy should commence 15 minutes after the last injection with 50 mg every 6 hours for 48 hours. Patients who fail to tolerate the full intravenous dose should be given half the suggested oral dose.
Renal impairment:
Dose adjustment is generally not needed in patients with impaired renal function.
Hepatic Impairment:
Dose adjustment is normally not needed in patients suffering from liver cirrhosis because metoprolol has a low protein binding (5 - 10 %). However, in patients with severe hepatic dysfunction a reduction in dosage may be necessary.
Elderly:
Several studies indicate that age related physiological changes have negligible effects on the pharmacokinetics of metoprolol. Dose adjustment is not needed in the elderly, but careful dose titration is important in all patients.
Paediatric population:
The safety and efficacy of metoprolol in children has not been established.
No special requirements.
